NORTREL 0.5/35-28
Clinical safety rating: caution
Comprehensive clinical and safety monograph for NORTREL 0.5/35-28 (NORTREL 0.5/35-28).
Norethindrone and ethinyl estradiol are a combination hormonal contraceptive. Norethindrone suppresses gonadotropin release (FSH and LH) from the pituitary, inhibiting ovulation. Ethinyl estradiol stabilizes the endometrium and enhances the contraceptive effect by inhibiting gonadotropin secretion.
| Metabolism | Norethindrone: primarily hepatic via reduction and sulfation; CYP3A4 involved. Ethinyl estradiol: hepatic via CYP3A4; undergoes first-pass metabolism and enterohepatic recirculation. |
| Excretion | Renal: ~40% as metabolites; Biliary/Fecal: ~60% as metabolites; <5% unchanged. |
| Half-life | Norethindrone: 7.2-9.2 hours; Ethinyl estradiol: 13-27 hours. Clinical context: Steady state reached in 5-7 days; half-life supports once-daily dosing. |
| Protein binding | Norethindrone: 61% bound to albumin, 36% to SHBG; Ethinyl estradiol: 97% bound to albumin, 2% free. |
| Volume of Distribution | Norethindrone: 3.6-4.3 L/kg; Ethinyl estradiol: 2.3-3.7 L/kg; indicates extensive tissue distribution. |
| Bioavailability | Oral: Norethindrone ~64% (extensive first-pass metabolism); Ethinyl estradiol ~43-45% (due to first-pass and gut wall metabolism). |
| Onset of Action | Oral: 24-48 hours for ovulation suppression; maximum effect after 7 days. |
| Duration of Action | 24 hours with once-daily dosing; contraceptive protection persists with consistent daily use; missed dose decreases protection. |
1 tablet orally once daily for 28 days (21 active tablets containing 0.5 mg norethindrone and 35 mcg ethinyl estradiol, followed by 7 placebo tablets).
| Dosage form | TABLET |
| Renal impairment | No dose adjustment required for GFR ≥30 mL/min. Use is not recommended in patients with GFR <30 mL/min or on dialysis due to potential decrease in hormone clearance and increased risk of adverse effects. |
| Liver impairment | Contraindicated in patients with Child-Pugh class B or C hepatic impairment. For Child-Pugh class A, use is not recommended due to potential reduced hormone metabolism. |
| Pediatric use | Not indicated for use in pediatric patients before menarche. For post-menarcheal adolescents, dosing is same as adults: 1 tablet orally once daily for 28 days. |
| Geriatric use | Not indicated for use in postmenopausal women. No specific dosing adjustments for elderly patients as the drug is not used in this population for contraception. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for NORTREL 0.5/35-28 (NORTREL 0.5/35-28).
| Breastfeeding | Norethindrone and ethinyl estradiol are excreted in breast milk. Estrogen components may reduce milk production. M/P ratio for norethindrone is approximately 0.7; ethinyl estradiol is <1. Use is generally not recommended during lactation. |
| Teratogenic Risk | First trimester: No increased risk of major birth defects based on large cohort studies. Second and third trimesters: Associated with masculinization of female fetuses (clitoral hypertrophy, labial fusion) and possible altered pubertal development. Risk of pseudohermaphroditism is dose-dependent. |
■ FDA Black Box Warning
Cigarette smoking increases the risk of serious cardiovascular events from combined hormonal contraceptive use. The risk increases with age and heavy smoking (≥15 cigarettes per day) and is significant in women over 35 years old. Women over 35 who smoke should not use combined hormonal contraceptives.
| Serious Effects |
["Known or suspected pregnancy","Current or history of venous thrombotic disease (deep vein thrombosis, pulmonary embolism)","Cerebrovascular or coronary artery disease","Current or history of migraine with aura (if age ≥35)","Breast cancer or other estrogen-sensitive neoplasia","Undiagnosed abnormal genital bleeding","Cholestatic jaundice of pregnancy or jaundice with prior oral contraceptive use","Active liver disease or benign/malignant liver tumors","Hypersensitivity to any component","Smoking cigarettes and age >35 years"]
| Precautions | ["Increased risk of thrombotic disorders (venous thromboembolism, stroke, myocardial infarction)","Hepatic neoplasia (benign and malignant)","Elevated blood pressure","Gallbladder disease","Carbohydrate/lipid metabolism effects","Headache/migraine","Irregular bleeding","Ocular changes (retinal thrombosis)","Depression","Hereditary angioedema","Pregnancy (discontinue if pregnancy occurs)"] |
Loading safety data…
| Fetal Monitoring |
| Monitor for fetal adrenal androgenization (ultrasound for ambiguous genitalia). Maternal monitoring: blood pressure, liver function, glucose tolerance, and signs of thromboembolism. |
| Fertility Effects | No permanent adverse effects on fertility. Reverses promptly after discontinuation. Contraindicated during confirmed pregnancy. |